Understanding the complexity of the immune system during pregnancy

American Journal of Reproductive Immunology

Volumn 72, Issue 2, 2014, Pages 107-116

  Racicot, Karen ^a   Kwon, Ja Young ^a   Aldo, Paulomi ^a   Silasi, Michelle ^a   Mor, Gil ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Immune regulation; Macrophages; Pregnancy; Trophoblast

Indexed keywords

BACTERIAL INFECTION; FETUS DEVELOPMENT; HUMAN; IMMUNE SYSTEM; PLACENTA; PLACENTA DISORDER; PREGNANCY; PREGNANCY OUTCOME; PREMATURE LABOR; PRIORITY JOURNAL; PROGENY; REVIEW; UROGENITAL TRACT INFECTION; UTERINE CERVIX DISEASE; VIRUS INFECTION; FEMALE; FETOMATERNAL TRANSFUSION; FETUS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; MICROBIOLOGY; VIROLOGY;

BACTERIAL INFECTIONS; FEMALE; FETUS; HUMANS; IMMUNE SYSTEM; IMMUNE TOLERANCE; MATERNAL-FETAL EXCHANGE; OBSTETRIC LABOR, PREMATURE; PLACENTA; PREGNANCY; VIRUS DISEASES;

EID: 84922831626     PISSN: 10467408     EISSN: 16000897     Source Type: Journal    
DOI: 10.1111/aji.12289     Document Type: Review

References (91)

1. Mor G, Cardenas I: The immune system in pregnancy: a unique complexity. Am J Reprod Immunol 2010; 63:425-433.
2. Ng SC, Gilman-Sachs A, Thaker P, Beaman KD, Beer AE, Kwak-Kim J: Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol 2002; 48:77-86.
3. Kwak-Kim JY, Gilman-Sachs A, Kim CE: T helper 1 and 2 immune responses in relationship to pregnancy, nonpregnancy, recurrent spontaneous abortions and infertility of repeated implantation failures. Chem Immunol Allergy 2005; 88:64-79.
4. Goldenberg RL, Culhane JF, Iams JD, Romero R: Epidemiology and causes of preterm birth. Lancet 2008; 371:75-84.
5. Jamieson DJ, Theiler RN, Rasmussen SA: Emerging infections and pregnancy. Emerg Infect Dis 2006; 12:1638-1643.
6. Digiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzun E, Relman DA: Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 2010; 64:38-57.
7. Guttmacher AE, Maddox YT, Spong CY: The Human Placenta Project: placental structure, development, and function in real time. Placenta 2014; 35:303-304.
8. Koga K, Cardenas I, Aldo P, Abrahams VM, Peng B, Fill S, Romero R, Mor G: Activation of TLR3 in the trophoblast is associated with preterm delivery. Am J Reprod Immunol 2009; 61:196-212.
9. Ashkar AA, Croy BA: Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy. Semin Immunol 2001; 13:235-241.
10. Croy BA, Di Santo JP, Greenwood JD, Chantakru S, Ashkar AA: Transplantation into genetically alymphoid mice as an approach to dissect the roles of uterine natural killer cells during pregnancy-a review. Placenta 2000; 21 Suppl A:S77-S80.
11. Zhang Q, Paria BC: Importance of uterine cell death, renewal, and their hormonal regulation in hamsters that show progesterone-dependent implantation. Endocrinology 2006; 147:2215-2227.
12. Koga K, Mor G: Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders. Am J Reprod Immunol 2010; 63:587-600.
13. Burke SD, Barrette VF, Gravel J, Carter AL, Hatta K, Zhang J, Chen Z, Leno-Duran E, Bianco J, Leonard S, Murrant C, Adams MA, Croy BA: Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am J Reprod Immunol 2010; 63:472-481.
14. Moffett-King A: Natural killer cells and pregnancy. Nat Rev Immunol 2002; 2:656-663.
15. Murphy SP, Fast LD, Hanna NN, Sharma S: Uterine NK Cells mediate inflammation-induced fetal demise in IL-10-null mice. J Immunol 2005; 175:4084-4090.
16. Thaxton JE, Sharma S: Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol 2010; 63:482-491.
17. Robertson SA, Skinner RJ, Care AS: Essential role for IL-10 in resistance to lipopolysaccharide-induced preterm labor in mice. J Immunol 2006; 177:4888-4896.
18. Plevyak M, Hanna N, Mayer S, Murphy S, Pinar H, Fast L, Ekerfelt C, Ernerudh J, Berg G, Matthiesen L, Sharma S: Deficiency of decidual IL-10 in first trimester missed abortion: a lack of correlation with the decidual immune cell profile. Am J Reprod Immunol 2002; 47:242-250.
19. Nagamatsu T, Schust DJ: The contribution of macrophages to normal and pathological pregnancies. Am J Reprod Immunol 2010; 63:460-471.
20. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM: M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000; 164:6166-6173.
21. Mantovani A, Sica A, Locati M: Macrophage polarization comes of age. Immunity 2005; 23:344-346.
22. Care AS, Diener KR, Jasper MJ, Brown HM, Ingman WV, Robertson SA: Macrophages regulate corpus luteum development during embryo implantation in mice. J Clin Invest 2013; 123:3472-3487.
23. Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G: Macrophages and apoptotic cell clearance during pregnancy. Am J Reprod Immunol 2004; 51:275-282.
24. Heikkinen J, Mottonen M, Komi J, Alanen A, Lassila O: Phenotypic characterization of human decidual macrophages. Clin Exp Immunol 2003; 131:498-505.
25. Hamilton S, Oomomian Y, Stephen G, Shynlova O, Tower CL, Garrod A, Lye SJ, Jones RL: Macrophages infiltrate the human and rat decidua during term and preterm labor: evidence that decidual inflammation precedes labor. Biol Reprod 2012; 86:39.
26. Aldo P, Racicot K, Craviero V, Guller S, Romero R, Mor G: Trophoblast inducesmonocyte differenciation into CD14+/CD16+ macrophages. Am J Reprod Immunol 2014; [Epub ahead of print].
27. Ramhorst R, Fraccaroli L, Aldo P, Alvero AB, Cardenas I, Leiros CP, Mor G: Modulation and recruitment of inducible regulatory T cells by first trimester trophoblast cells. Am J Reprod Immunol 2012; 67:17-27.
28. Abrahams VM, Fahey JV, Schaefer TM, Wright JA, Wira CR, Mor G: Stimulation of first trimester trophoblast cells with Poly(I:C) induces SLPI secretion. Am J Reprod Immunol 2005; 53:280 ASRI205-204.
29. Abrahams VM, Romero R, Mor G: TLR-3 and TLR-4 mediate differential chemokine production and immune cell recruitment by first trimester trophoblast cells. Am J Reprod Immunol 2005; 53:279-ASRI205-202.
30. Mor G, Romero R, Aldo PB, Abrahams VM: Is the trophoblast an immune regulator?: the role of toll-like receptors during pregnancy. Crit Rev Immunol 2005; 25:375-388.
31. Costello MJ, Joyce SK, Abrahams VM: NOD protein expression and function in first trimester trophoblast cells. Am J Reprod Immunol 2007; 57:67-80.
32. Fest S, Aldo PB, Abrahams VM, Visintin I, Alvero A, Chen R, Chavez SL, Romero R, Mor G: Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy. Am J Reprod Immunol 2007; 57:55-66.
33. Ivashkiv LB, Donlin LT: Regulation of type I interferon responses. Nat Rev Immunol 2014; 14:36-49.
34. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G: TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007; 131:1124-1136.
35. Kovarik P, Sauer I, Schaljo B: Molecular mechanisms of the anti-inflammatory functions of interferons. Immunobiology 2007; 212:895-901.
36. Frobose H, Ronn SG, Heding PE, Mendoza H, Cohen P, Mandrup-Poulsen T, Billestrup N: Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. Mol Endocrinol 2006; 20:1587-1596.
37. Hanada T, Yoshida H, Kato S, Tanaka K, Masutani K, Tsukada J, Nomura Y, Mimata H, Kubo M, Yoshimura A: Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity. Immunity 2003; 19:437-450.
38. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O'Neill LA, Hertzog PJ: Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 2006; 7:148-155.
39. Johnson KP, Panitch HS: Interferon therapy for multiple sclerosis. Md Med J 1992; 41:601-603.
40. Weinstock-Guttman B, Jacobs LD: What is new in the treatment of multiple sclerosis? Drugs 2000; 59:401-410.
41. Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL: A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992; 166:1515-1528.
42. Han YW, Redline RW, Li M, Yin L, Hill GB, McCormick TS: Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice: implication of oral bacteria in preterm birth. Infect Immun 2004; 72:2272-2279.
43. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S: The role of inflammation and infection in preterm birth. Semin Reprod Med 2007; 25:21-39.
44. Romero R, Brody DT, Oyarzun E, Mazor M, Wu YK, Hobbins JC, Durum SK: Infection and labor. III. Interleukin-1: a signal for the onset of parturition. Am J Obstet Gynecol 1989; 160:1117-1123.
45. Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, Sabo V, Athanassiadis AP, Hobbins JC: Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 1989; 161:817-824.
46. Watari M, Watari H, DiSanto ME, Chacko S, Shi GP, Strauss JF 3rd: Pro-inflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. Am J Pathol 1999; 154:1755-1762.
47. Fichorova RN: Guiding the vaginal microbicide trials with biomarkers of inflammation. J Acquir Immune Defic Syndr 2004; 37(Suppl 3):S184-S193.
48. Fichorova RN, Onderdonk AB, Yamamoto H, Delaney ML, DuBois AM, Allred E, Leviton A: Maternal microbe-specific modulation of inflammatory response in extremely low-gestational-age newborns. MBio 2011; 2:e00280-00210.
49. Fichorova RN, Yamamoto HS, Delaney ML, Onderdonk AB, Doncel GF: Novel vaginal microflora colonization model providing new insight into microbicide mechanism of action. MBio 2011; 168-179.
50. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J: The placenta harbors a unique microbiome. Sci Transl Med 2014; 6:237ra265.
51. Hajishengallis G, Lambris JD: Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol 2011; 11:187-200.
52. Bakaletz LO: Developing animal models for polymicrobial diseases. Nat Rev Microbiol 2004; 2:552-568.
53. Smith H: The role of microbial interactions in infectious disease. Philos Trans R Soc Lond B Biol Sci 1982; 297:551-561.
54. Cardenas I, Aldo P, Koga K, Means R, Lang SH, Mor G: Subclinicla viral infection in pregnancy lead to inflammatoruy process at the placenta with non-lethal fetal damage. Am J Reprod Immunol 2009; 61:397-S312.
55. Cardenas I, Mor G, Aldo P, Lang SM, Stabach P, Sharp A, Romero R, Mazaki-Tovi S, Gervasi M, Means RE: Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis. Am J Reprod Immunol 2010; 61:397-S12.
56. Olivadoti M, Toth LA, Weinberg J, Opp MR: Murine gammaherpesvirus 68: a model for the study of Epstein-Barr virus infections and related diseases. Comp Med 2007; 57:44-50.
57. Murphy SP, Hanna NN, Fast LD, Shaw SK, Berg G, Padbury JF, Romero R, Sharma S: Evidence for participation of uterine natural killer cells in the mechanisms responsible for spontaneous preterm labor and delivery. Am J Obstet Gynecol 2009; 200:308 e301-e309.
58. Srinivas SK, Ma Y, Sammel MD, Chou D, McGrath C, Parry S, Elovitz MA: Placental inflammation and viral infection are implicated in second trimester pregnancy loss. Am J Obstet Gynecol 2006; 195:797-802.
59. Kourtis AP, Read JS, Jamieson DJ: Pregnancy and infection. N Engl J Med 2014; 370:2211-2218.
60. Racicot K, Cardenas I, Wunsche V, Aldo P, Guller S, Means RE, Romero R, Mor G: Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol 2013; 191:934-941.
61. Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH: Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav Immun 2001; 15:411-420.
62. Cardenas I, Means RE, Aldo P, Koga K, Lang SM, Booth C, Manzur A, Oyarzun E, Romero R, Mor G: Viral Infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol 2010; 185:1247-1257.
63. Davies JK, Shikes RH, Sze CI, Leslie KK, McDuffie RS Jr, Romero R, Gibbs RS: Histologic inflammation in the maternal and fetal compartments in a rabbit model of acute intra-amniotic infection. Am J Obstet Gynecol 2000; 183:1088-1093.
64. Salaun B, Romero P, Lebecque S: Toll-like receptors' two-edged sword: when immunity meets apoptosis. Eur J Immunol 2007; 37:3311-3318.
65. Madsen-Bouterse SA, Romero R, Tarca AL, Kusanovic JP, Espinoza J, Kim CJ, Kim JS, Edwin SS, Gomez R, Draghici S: The transcriptome of the fetal inflammatory response syndrome. Am J Reprod Immunol 2010; 63:73-92.
66. Deverman BE, Patterson PH: Cytokines and CNS development. Neuron 2009; 64:61-78.
67. Shi L, Smith SE, Malkova N, Tse D, Su Y, Patterson PH: Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav Immun 2009; 23:116-123.
68. Meyer U, Feldon J, Yee BK: A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull 2009; 35:959-972.
69. Golan HM, Lev V, Hallak M, Sorokin Y, Huleihel M: Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy. Neuropharmacology 2005; 48:903-917.
70. Espinoza J, Erez O, Romero R: Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery. Am J Obstet Gynecol 2006; 194:630-637.
71. Hickey DK, Fahey JV, Wira CR: Mouse estrous cycle regulation of vaginal versus uterine cytokines, chemokines, alpha-/beta-defensins and TLRs. Innate Immun 2012; 19:121-131.
72. Wira CR, Fahey JV, Ghosh M, Patel MV, Hickey DK, Ochiel DO: Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol 2010; 63:544-565.
73. Lee DC, Hassan SS, Romero R, Tarca AL, Bhatti G, Gervasi MT, Caruso JA, Stemmer PM, Kim CJ, Hansen LK, Becher N, Uldbjerg N: Protein profiling underscores immunological functions of uterine cervical mucus plug in human pregnancy. J Proteomics 2011; 74:817-828.
74. Cooper MD, Roberts MH, Barauskas OL, Jarvis GA: Secretory leukocyte protease inhibitor binds to Neisseria gonorrhoeae outer membrane opacity protein and is bactericidal. Am J Reprod Immunol 2012; 68:116-127.
75. Becher N, Adams Waldorf K, Hein M, Uldbjerg N: The cervical mucus plug: structured review of the literature. Acta Obstet Gynecol Scand 2009; 88:502-513.
76. Hein M, Valore EV, Helmig RB, Uldbjerg N, Ganz T: Antimicrobial factors in the cervical mucus plug. Am J Obstet Gynecol 2002; 187:137-144.
77. Nasu K, Narahara H: Pattern recognition via the toll-like receptor system in the human female genital tract. Mediators Inflamm 2010; 2010:976024.
78. Hertz CJ, Wu Q, Porter EM, Zhang YJ, Weismuller KH, Godowski PJ, Ganz T, Randell SH, Modlin RL: Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2. J Immunol 2003; 171:6820-6826.
79. Homma T, Kato A, Hashimoto N, Batchelor J, Yoshikawa M, Imai S, Wakiguchi H, Saito H, Matsumoto K: Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells. Am J Respir Cell Mol Biol 2004; 31:463-469.
80. Kaushic C: HIV-1 infection in the female reproductive tract: role of interactions between HIV-1 and genital epithelial cells. Am J Reprod Immunol 2011; 65:253-260.
81. You H, Liu Y, Agrawal N, Prasad CK, Edwards JL, Osborne AF, Korourian S, Lowery CL, Hermonat PL: Multiple human papillomavirus types replicate in 3A trophoblasts. Placenta 2008; 29:30-38.
82. Gomez LM, Ma Y, Ho C, McGrath CM, Nelson DB, Parry S: Placental infection with human papillomavirus is associated with spontaneous preterm delivery. Hum Reprod 2008; 23:709-715.
83. Zuo Z, Goel S, Carter JE: Association of cervical cytology and HPV DNA status during pregnancy with placental abnormalities and preterm birth. Am J Clin Pathol 2011; 136:260-265.
84. Caserta MT, Hall CB, Schnabel K, Lofthus G, McDermott MP: Human herpesvirus (HHV)-6 and HHV-7 infections in pregnant women. J Infect Dis 2007; 196:1296-1303.
85. Tanaka K, Yamada H, Minami M, Kataoka S, Numazaki K, Minakami H, Tsutsumi H: Screening for vaginal shedding of cytomegalovirus in healthy pregnant women using real-time PCR: correlation of CMV in the vagina and adverse outcome of pregnancy. J Med Virol 2006; 78:757-759.
86. Barker DJ: Maternal and fetal origins of coronary heart disease. J R Coll Physicians Lond 1994; 28:544-551.
87. Gilmore W, Weiner LP, Correale J: Effect of estradiol on cytokine secretion by proteolipid protein- specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997; 158:446-451.
88. Brown AS, Begg MD, Gravenstein S, Schaefer CA, Wyatt RJ, Bresnahan M, Babulas VP, Susser ES: Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry 2004; 61:774-780.
89. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M: Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 2007; 36:361-365.
90. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA: Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57:67-81.
91. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH: Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007; 27:10695-10702.